Publications (9)20.91 Total impact
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Article: Potent, exceptionally selective, orally bioavailable inhibitors of TNF-alpha Converting Enzyme (TACE): novel 2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamide P1' substituents.
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ABSTRACT: Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.Bioorganic & medicinal chemistry letters 04/2008; 18(5):1577-82. · 2.65 Impact Factor -
Article: Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE): discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1' substituents.
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ABSTRACT: Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.Bioorganic & medicinal chemistry letters 04/2008; 18(6):1958-62. · 2.65 Impact Factor -
Article: Alpha,Beta-cyclic-beta-benzamido hydroxamic acids: Novel oxaspiro[4.4]nonane templates for the discovery of potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
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ABSTRACT: Two novel oxaspiro[4.4]nonane beta-benzamido hydroxamic scaffolds have been synthesized in enantio- and diasteriomerically pure form. These templates proved to be exceptional platforms that have led to the discovery of potent inhibitors of TACE that are active in a cellular assay measuring suppression of LPS-induced TNF-alpha. Furthermore, these inhibitors are selective against related MMPs, demonstrate permeability in a Caco-2 assay, and display good oral bioavailability.Bioorganic & medicinal chemistry letters 03/2008; 18(4):1288-92. · 2.65 Impact Factor -
Article: Alpha,beta-cyclic-beta-benzamido hydroxamic acids: novel templates for the design, synthesis, and evaluation of selective inhibitors of TNF-alpha converting enzyme (TACE).
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ABSTRACT: Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.Bioorganic & medicinal chemistry letters 02/2008; 18(2):694-9. · 2.65 Impact Factor -
Article: Discovery of beta-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors.
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ABSTRACT: Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.Bioorganic & medicinal chemistry letters 02/2008; 18(1):241-6. · 2.65 Impact Factor -
Article: Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors.
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ABSTRACT: A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.Bioorganic & Medicinal Chemistry Letters 06/2006; 16(10):2699-704. · 2.55 Impact Factor -
Article: Synthesis and structure-activity relationship of a novel sulfone series of TNF-alpha converting enzyme inhibitors.
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ABSTRACT: Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-[[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl]-4-pyrrolidinecarboxamide) exhibited IC50 values of < 1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP-1, -2, -9 and -13 and was orally bioavailable with an F value of 46% in mice.Bioorganic & Medicinal Chemistry Letters 10/2004; 14(17):4453-9. · 2.55 Impact Factor -
Article: Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 2: lead optimization.
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ABSTRACT: Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.Bioorganic & Medicinal Chemistry Letters 01/2004; 13(24):4299-304. · 2.55 Impact Factor -
Article: Discovery of β-benzamido hydroxamic acids as potent, selective, and orally bioavailable TACE inhibitors
Bioorganic & Medicinal Chemistry Letters. 18(1):241-246.
Top co-authors
Top Journals
Institutions
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2008
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Cephalon Inc.
Malvern, PA, USA
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2004–2008
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Bristol-Myers Squibb
New York City, NY, USA
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